An important goal of cancer immunotherapy is to generate long-lived memory T cells to provide long-term immunity against cancer. However, it is virtually unknown what controls the formation of tumor-specific memory T cells. Thus, understanding and exploiting mechanisms underlying the induction of long-lasting memory T cell immunity is crucial to the development of vaccines and immunotherapies for the prevention and treatment of cancers in humans. The objective of this application is to elucidate critical mechanisms governing the formation of long-lived, tumor-specific memory CD8 T cells. Specifically, we hypothesize that NK cells are critical for the generation of long-lived, tumor-specific CD8 memory T cells. We will test this hypothesis with four specific aims and pursue the mechanisms underlying NK cell-dependent formation of long-lived memory CD8 T cells in two different tumor models. By providing molecular and cellular basis for the formation of long- lived, tumor-specific CD8 memory T cells, these studies will substantially increase knowledge of critical factors responsible for the generation of long-lasting anti-tumor immunity. Thus, the outcomes of this proposal will have significant impact on the design of effective vaccine strategies for treating cancer and preventing relapses, leading to the potential cure of cancer. Furthermore, the principles learned here can be applied to the memory T cell field in general for the treatment of other diseases such as pathogenic infections.